Epstein-Barr virus (EBV), also referred to as human herpesvirus 4 (HHV-4), is the principle etiological agent of infectious mononucleosis (IM) and is also associated with several human cancers, with more than 300,000 people being affected each year worldwide. The World Health Organization estimates that 95% of adults worldwide have been infected with EBV and are carriers of the virus. For the majority of individuals, EBV does not cause any symptoms and is indistinguishable from common, mild childhood illnesses. Currently, there is no vaccine for EBV. However, prevention of IM and EBV-associated malignancies through vaccination would have a substantial public health and economic benefit.
EBV has a linear, double-stranded DNA genome comprising approximately 192 kilobases (KB) of DNA, surrounded by a protein capsid. The capsid is surrounded by a protein tegument, which in turn is surrounded by an envelope. The EBV envelope contains several proteins, including glycoprotein gp350, gH, gB, gM, gp42, gL, gp78, gp150 and gN. The most abundant envelope glycoprotein is 350/220 (gp350), which binds complement receptor 2 (CR2 or CD21) enabling EBV infection of B cells, while glycoproteins gH and gp42 bind integrins and human leukocyte antigen class II molecules, respectively. Antibodies directed toward the putative CR2-binding site (CR2BS) on gp350 have been shown to potently inhibit EBV infections of B cells, and thus vaccine efforts against EBV have been largely focused on gp350.
In addition to infecting B cells, EBV also infects epithelial cells in the oropharynx where it is thought to spread to B cells. Current data suggests that infection of epithelial cells by EBV is initiated by attachment of EBV BMRF2 protein to epithelial cells followed by binding of EBV gH/gL to integrins, which serve as receptors for the virus on epithelial cells. Antibodies to gH/gL in human plasma blocks EBV infection of epithelial cells (Bu and Cohen, unpublished data) suggesting that a vaccine capable of inducing antibodies to EBV gH/gL may help to prevent infection or human disease due to EBV.
While work on EBV vaccines has continued, to date there is no efficacious EBV vaccine. For example, a recently completed phase 2 clinical trial of an adjuvanted recombinant gp350 protein vaccine showed that the vaccine did not protect against EBV infection but did reduce the incidence of IM by 78% (Sokal, E. M., et al. J Infect Dis. 196:1749-53, 2007). Thus, there remains a need for an efficacious Epstein-Barr virus vaccine that provides robust protection against EBV. The present invention meets this need by providing a novel ENV-SA protein-based nanoparticle (ENV-SA np) vaccine that is easily manufactured, potent, and elicits neutralizing antibodies against EBV.